May isoflavones prevent breast cancer risk?

Breast cancer still represents a challenge in Brazil, as it is the most frequent malignant neoplasm with more than 14,000 deaths recorded in 2014. It is the leading cause of death in the female population¹. It is also commonly diagnosed among women in Western countries as the second leading cause of cancer². It is the sixth leading cause of mortality among women, after acute myocardial infarction, pneumonia, diabetes, stroke, and chronic obstructive pulmonary disease. Breast cancer is a heterogeneous disease and can be classified by clinical, histopathological, and molecular parameters³. In this classification, the estrogen receptors play an important role and seem to influence the development of breast neoplasms or response to treatment⁴. However, women with breast cancer face the consequences of hypoestrogenism due to chemotherapy treatment or being postmenopausal. Thus, several substances are being suggested to reduce the vasomotor symptoms that appear in these women.

The effects of soy isoflavones, due to their structural similarity and molecular size that resemble estrogens, have the ability to bind with greater affinity to estrogen beta-receptors; for this reason, they are called phytoestrogens⁵–⁷. The binding of phytoestrogen to the receptor can result in partial activation of the receptor (agonist effect) or displacement of estrogen molecules, thus reducing receptor activation (antagonistic effect)⁸.

Intake of soy at high dosages may have a statistically significant reduction in breast cancer risk⁹. Epidemiological studies show that soy consumption is associated with low incidences of hormone-dependent cancers, including breast and prostate cancer in Western countries¹⁰. However, there are other components in soy that can also have a biological effect and there is a substitution in these countries of animal protein for soy protein. Therefore, this is still a controversial point¹¹.

Soy contains large amounts of isoflavones, such as genistein and daidzein. Genistein, one of the predominant soy isoflavones, may inhibit several steps involved in carcinogenesis by targeting estrogen- and androgen-mediated signaling pathways in carcinogenesis processes, in addition to its antioxidant properties showing to be a potent inhibitor of angiogenesis and metastasis¹²,¹³. In vivo and in vitro studies have clearly shown that genistein is a promising reagent for the chemoprevention and/or treatment of cancer. However, results are still conflicting and there is still no consensus on its effectiveness on the breast cancer risk¹¹,¹⁴,¹⁵.

Prospective cohort meta-analysis studies suggest that high soy intakes may statistically reduce the risk of breast cancer⁹, other systematic and meta-analysis reviews conclude that there is a lack of evidence as the benefit would be small and irrelevant in clinical practice¹⁶. Thus, further prospective cohort studies are needed to determine the causality of this relationship, as well as to explain the mechanisms involved in the association between isoflavones and breast cancer⁹.

A randomized, double-blind, placebo-controlled clinical trial conducted by Delmanto et al.¹⁷ determined the effect of soy isoflavones on breast density and breast parenchyma assessed by mammography in 80 postmenopausal women. After 10 months of isoflavone supplementation, it was found that daily intake of 100 mg isoflavones did not affect breast density (assessed by mammography) and breast tissues (assessed by ultrasound).

Khan et al.¹⁸ evaluated the effect of soy isoflavone supplementation on breast epithelial proliferation and other biomarkers in high-risk, healthy Western women. The breast cell proliferation is an intermediate marker of breast cancer risk generally considered more reflective of risk than mammographic density. Cells were examined for Ki-67 labeling index and atypia. The study involved 98 pre- and postmenopausal women. After 6 months of isoflavone supplementation, the authors found that daily intake of 235 mg of isoflavones did not increase cell proliferation in pre- and postmenopausal women compared with placebo. In contrast, a hormone therapy combination increased breast cell proliferation in postmenopausal womenhan¹⁹.

Although there is a greater consumption of soy and isoflavones worldwide, it is still too early to understand the real impact of these substances on the reduction of the risk of incidence, recurrence, and mortality from breast cancer. There is no enough evidence in the literature of serious adverse effects such as increased risk for breast cancer and cardiovascular disease with the use of isoflavones in high doses (≤100 mg)²⁰. Although studies on herbal medicine are still in progress, there are only a few still many myths to overcome²¹.

The extramammary benefits of soy are evident as in vasomotor symptoms²², skin²³, bone mass²⁴, and genital tract²⁵.

However, the risk of breast cancer needs to be better explored and evaluated, mainly in the long term, and there are still risks that should be better evaluated, such as metabolic ones. In addition, the indication of isoflavone extracts should be individualized, as estroprogestative hormone therapy in the climacteric²⁶, guiding the patient on the benefits and risks, as well as respecting the individual preferences of postmenopausal women until new evidences in the literature.

• Funding: none.

REFERENCES

• ¹
  Instituto Nacional De Câncer José Alencar Gomes Da Silva. Atlas da mortalidade. Rio de Janeiro: Instituto Nacional De Câncer José Alencar Gomes Da Silva; 2020. Available from: https://www.inca.gov.br/app/mortalidade
  » https://www.inca.gov.br/app/mortalidade
• ²
  Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. https://doi.org/10.1038/s41572-019-0111-2
  » https://doi.org/10.1038/s41572-019-0111-2
• ³
  DATASUS. Informações de saúde. Available from: http://www2.datasus.gov.br
  » http://www2.datasus.gov.br
• ⁴
  Liang J, Shang Y. Estrogen and cancer. Annu Rev Physiol. 2013;75:225-40. https://doi.org/10.1146/annurev-physiol-030212-183708
  » https://doi.org/10.1146/annurev-physiol-030212-183708
• ⁵
  Křížová L, Dadáková K, Kašparovská J, Kašparovský T. Isoflavones. Molecules. 2019;24(6):1076. https://doi.org/10.3390/molecules24061076
  » https://doi.org/10.3390/molecules24061076
• ⁶
  Chen MN, Lin CC, Liu CF. Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric. 2015;18(2):260-9. https://doi.org/10.3109/13697137.2014.966241
  » https://doi.org/10.3109/13697137.2014.966241
• ⁷
  Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 2006;55(1):1-12. https://doi.org/10.1207/s15327914nc5501_1
  » https://doi.org/10.1207/s15327914nc5501_1
• ⁸
  Castelo-Branco C, Cancelo Hidalgo MJ. Isoflavones: effects on bone health. Climacteric. 2011;14(2):204-11. https://doi.org/10.3109/13697137.2010.529198
  » https://doi.org/10.3109/13697137.2010.529198
• ⁹
  Zhao TT, Jin F, Li JG, Xu YY, Dong HT, Liu Q, et al. Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: a meta-analysis of prospective cohort studies. Clin Nutr. 2019;38(1):136-45. https://doi.org/10.1016/j.clnu.2017.12.006
  » https://doi.org/10.1016/j.clnu.2017.12.006
• ¹⁰
  Pabich M, Materska M. Biological effect of soy isoflavones in the prevention of civilization diseases. Nutrients. 2019;11(7):1660. https://doi.org/10.3390/nu11071660
  » https://doi.org/10.3390/nu11071660
• ¹¹
  Kaari C, Haidar MA, Júnior JM, Nunes MG, Quadros LG, Kemp C, et al. Randomized clinical trial comparing conjugated equine estrogens and isoflavones in postmenopausal women: a pilot study. Maturitas. 2006;53(1):49-58. https://doi.org/10.1016/j.maturitas.2005.02.009
  » https://doi.org/10.1016/j.maturitas.2005.02.009
• ¹²
  Varinska L, Gal P, Mojzisova G, Mirossay L, Mojzis J. Soy and breast cancer: focus on angiogenesis. Int J Mol Sci. 2015;16(5):11728-49. https://doi.org/10.3390/ijms160511728
  » https://doi.org/10.3390/ijms160511728
• ¹³
  Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest. 2003;21(5):744-57. https://doi.org/10.1081/cnv-120023773
  » https://doi.org/10.1081/cnv-120023773
• ¹⁴
  Bedell S, Nachtigall M, Naftolin F. The pros and cons of plant estrogens for menopause. J Steroid Biochem Mol Biol. 2014;139:225-36. https://doi.org/10.1016/j.jsbmb.2012.12.004
  » https://doi.org/10.1016/j.jsbmb.2012.12.004
• ¹⁵
  Carbonel AA, Santos RH, Simões RS, Silva RF, Soares JM Jr, Baracat EC, et al. Efeitos de altas doses de genisteína sobre o epitélio mamário de ratas [Effects of high doses of genistein on mammary gland of female rat]. Rev Bras Ginecol Obstet. 2011;33(9):264-9. https://doi.org/10.1590/s0100-72032011000900008
  » https://doi.org/10.1590/s0100-72032011000900008
• ¹⁶
  Qiu S, Jiang C. Soy and isoflavones consumption and breast cancer survival and recurrence: a systematic review and meta-analysis. Eur J Nutr. 2019;58(8):3079-90. https://doi.org/10.1007/s00394-018-1853-4
  » https://doi.org/10.1007/s00394-018-1853-4
• ¹⁷
  Delmanto A, Nahas-Neto J, Traiman P, Uemura G, Pessoa EC, Nahas EA. Effects of soy isoflavones on mammographic density and breast parenchyma in postmenopausal women: a randomized, double-blind, placebo-controlled clinical trial. Menopause. 2013;20(10):1049-54. https://doi.org/10.1097/GME.0b013e3182850270
  » https://doi.org/10.1097/GME.0b013e3182850270
• ¹⁸
  Khan SA, Chatterton RT, Michel N, Bryk M, Lee O, Ivancic D, et al. Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial. Cancer Prev Res (Phila). 2012;5(2):309-19. https://doi.org/10.1158/1940-6207.CAPR-11-0251
  » https://doi.org/10.1158/1940-6207.CAPR-11-0251
• ¹⁹
  Murkes D, Conner P, Leifland K, Tani E, Beliard A, Lundstrom E, et al. Efeitos da progesterona oral-estradiol percutânea versus estrogênios equinos conjugados orais-acetato de medroxiprogesterona na proliferação de células mamárias e BCL-2 proteína em mulheres saudáveis. Fértil Esteril. 2011;95(3):1188-91. https://doi.org/10.1016/j.fertnstert.2010.09.062
  » https://doi.org/10.1016/j.fertnstert.2010.09.062
• ²⁰
  Fritz H, Seely D, Flower G, Skidmore B, Fernandes R, Vadeboncoeur S, et al. Soy, red clover, and isoflavones and breast cancer: a systematic review. PLoS One. 2013;8(11):e81968. https://doi.org/10.1371/journal.pone.0081968
  » https://doi.org/10.1371/journal.pone.0081968
• ²¹
  Lopes CMC, Lima SMRR, Veiga ECA, Soares-Jr JM, Baracat EC. Phytotherapeutic medicines: reality or myth? Rev Assoc Med Bras (1992). 2019;65(3):292-4. https://doi.org/10.1590/1806-9282.65.3.292
  » https://doi.org/10.1590/1806-9282.65.3.292
• ²²
  Han KK, Soares JM Jr, Haidar MA, de Lima GR, Baracat EC. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99(3):389-94. https://doi.org/10.1016/s0029-7844(01)01744-6
  » https://doi.org/10.1016/s0029-7844(01)01744-6
• ²³
  Accorsi-Neto A, Haidar M, Simões R, Simões M, Soares J Jr, Baracat E. Effects of isoflavones on the skin of postmenopausal women: a pilot study. Clinics (Sao Paulo). 2009;64(6):505-10. https://doi.org/10.1590/s1807-59322009000600004
  » https://doi.org/10.1590/s1807-59322009000600004
• ²⁴
  Carbonel AAF, Vieira MC, Simões RS, Lima PDA, Fuchs LFP, Girão ERC, et al. Isoflavones improve collagen I and glycosaminoglycans and prevent bone loss in type 1 diabetic rats. Climacteric. 2020;23(1):75-83. https://doi.org/10.1080/13697137.2019.1627314
  » https://doi.org/10.1080/13697137.2019.1627314
• ²⁵
  Franco PC, Simões RS, Carbonel AAF, Sasso GRDS, Florencio-Silva R, Baracat EC, et al. The influence of phytoestrogens or estrogens on the proliferation of the rat endocervical mucosa. Rev Assoc Med Bras (1992). 2020;66(2):174-9. https://doi.org/10.1590/1806-9282.66.2.174
  » https://doi.org/10.1590/1806-9282.66.2.174
• ²⁶
  Soares Júnior JM, Sorpreso IC, Baracat EC. Is hormone therapy during climacteric for all? Rev Assoc Med Bras (1992). 2015;61(3):191-2. https://doi.org/10.1590/1806-9282.61.03.191
  » https://doi.org/10.1590/1806-9282.61.03.191

Publication Dates

• Publication in this collection
  28 Nov 2022
• Date of issue
  2022

History

• Received
  18 July 2022
• Accepted
  31 July 2022